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Microenvironment and Immunology

The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma

Juan Wu, Jiaqi Li, Rosalba Salcedo, Nahid F. Mivechi, Giorgio Trinchieri and Anatolij Horuzsko
Juan Wu
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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Jiaqi Li
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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Rosalba Salcedo
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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Nahid F. Mivechi
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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Giorgio Trinchieri
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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Anatolij Horuzsko
Authors' Affiliations: 1Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia; and 2Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH; and 3SAIC-Frederick, Inc., Frederick, Maryland
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DOI: 10.1158/0008-5472.CAN-12-0938 Published August 2012
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    Figure 1.

    Deletion of TREM-1 decreases DEN-induced liver tumorigenesis. A, WT and Trem1−/− male mice were given a dose of DEN (25 mg/kg) at 15 days of age. Numbers of tumors (≥0.5 mm) and maximal tumor sizes (diameters) in livers of WT (n = 9) and Trem1−/− (n = 7) mice 8 months after DEN injection; ND, not detectable. Bars represent mean ± SD, statistical significance is indicated (***P < 0.001). One of 2 similar experiments is shown. B, numbers of tumors and maximal tumor sizes in livers of male WT (n = 7) and Trem1−/− (n = 10) mice 14 months after DEN injection. Bars represent mean ± SD, and statistical significance is indicated (**P < 0.01, *** P < 0.001). One of 2 independent experiments with similar results is shown. Representative microscopic pictures of livers from WT, Trem1−/− mice 8 months (C) and 14 months (D) after DEN injection. Arrowhead indicates tumor nodules. E, histologic analysis (hematoxylin and eosin) of livers from indicated mice 8 months (E) and 14 months (F) after injection of DEN; N, noncancerous liver tissues; T, tumors. Arrowheads indicate border between noncancerous liver tissues and tumor; original magnification, ×10. Bars, 50 μm. The expression of HCC marker α-fetoprotein (AFP) by liver tumor cells determined by immunohistochemistry (G) and by Western blot analysis (H) using an anti-AFP antibody; bar, 20 μm. One of 2 similar experiments is shown.

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    Figure 2.

    TREM-1 deficiency decreases of DEN-induced hepatic injury. WT and Trem1−/− male mice were treated for 4 hours with DEN (100 mg/kg) or left untreated. A and B, livers of WT or Trem1−/− mice were assessed for apoptosis by TUNEL staining. Original magnification, ×40. Values are mean ± SD for independent animals (n = 5). One of 4 similar experiments is shown. C, levels of IL-6 and ALT (F) in serum of WT and Trem1−/− mice treated with DEN at indicated time. D and E, hepatocyte proliferation in livers of WT or Trem1−/− mice was assessed by injecting mice with BrdUrd (1 mg/mL) 2 hours before the liver was removed. BrdUrd-positive cells were identified by immunostaining. Original magnification, ×40. Values are mean ± SD for independent animals (n = 3). One of 3 similar experiments is shown. Data are shown as mean ± SD (n = 5 mice per group). For all panels statistical significance is indicated (*P < 0.05, **P < 0.01); h, hour. One of 4 similar experiments is shown.

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    Figure 3.

    Loss of TREM-1 alters recruitment of neutrophils and monocytes. Bone marrow, blood, and liver samples of indicated mice were stained with appropriate mAbs and analyzed by flow cytometry. Data are shown as mean ± SD (n = 3 mice per group) of neutrophils (CD11bhigh, Ly6G+; A) and monocytes (CD11b+, Ly6Chigh; B) and represent 1 experiment of 3 independent experiments with similar results.

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    Figure 4.

    TREM-1 deletion alters activation of Kupffer cells in response to DEN and decreases expression of genes involved in inflammatory responses, cell-cycle regulation and apoptosis. A, WT and Trem1−/− male mice (n = 10 mice per group) were treated for 4 hours with DEN. Cells from total livers, isolated hepatocytes, or Kupffer cells were subjected to RNA isolation and microarray analysis. The average fold induction/decrease was obtained by comparison of Trem1−/− mice with WT mice. Fold changes in proinflammatory cytokine and chemokine gene expression (A), in genes related to NF-κB signaling pathway (B), and in genes related to JNK/p38 signaling pathway (C) are shown. Shown is one representative experiment from 2 independent experiments. Values are mean ± SD. D–F, WT and Trem1−/− mice were treated for 4 hours with DEN or left untreated (n = 4 mice per group). RNA samples extracted from livers were subjected to NanoString analysis. Decreased expression in genes involved in inflammation (D), cell-cycle regulation (E), and apoptosis (F) was observed in Trem1−/− mice post-DEN treatment. The results are expressed as mean ± SE. Statistical significance is indicated.

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    Figure 5.

    Adoptively transferred Kupffer cells from WT mice increased DEN-induced liver injury in Trem1−/− mice. A, immunofluorescence staining of liver sections with FITC-conjugated anti-F4/80 mAb after 48-hour injection of clodronate-containing liposomes. D, reconstitution of predepleted livers with Kupffer cells from WT mice to indicated mice. Adoptively transferred cells were observed at 18 hours by immunofluorescence staining; bar, 20 μm. Mice were given a dose of DEN at 18 hours after Kupffer cell reconstitution and ALT (B) and IL-6 (C) in serum were measured at indicated time. Data shown are means ± SD of 4 mice per group and representative of 2 independent experiments. E and F, 4 hours after DEN treatment gene expression profile of reconstituted liver was carried out using NanoString Technology. Values indicate mean ± SE of 4 mice per time point in each group. ns, not statistically significant.

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    Figure 6.

    TREM-1 binds HMGB1. A, HMGB1 and HSP70 present in the production of necrotic hepatocytes (PNH). PNH were isolated from DEN-treated and nontreated WT mice and subjected to Western blot analysis with indicated antibodies. Actin was used as a loading control. B, HMGB1 and not HSP70 associated with TREM-1. Necrotic hepatocytes isolated from DEN-treated WT mice were subjected to immunoprecipitation with murine recombinant TREM-1-Fc fusion protein followed by immunoblotting with indicated antibodies. C, purified murine HMGB1 and TREM-1 proteins were used as cross-linked proteins. Cross-linking reactions with bis(sulfosuccinimidyl) suberate (BS3, left) or dimethyl adipimidate (DMA, right). One of 4 similar experiments is shown. D, SPR analysis of TREM-1 and RAGE binding to immobilized HMGB1. The concentrations of RAGE (0, black; 30, yellow; 60, gray; 120, blue; and 240 nmol/L, red (left); the identical concentrations of TREM-1 and CsrA were flowed over immobilized HMGB1 on the sensor chip. Data are presented as response units (RU) over time (seconds). Data shown are representative of 3 experiments.

Additional Files

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    Files in this Data Supplement:

    • Supplementary Methods - PDF file - 102K
    • Supplementary Figure 1 - PDF file - 2.9MB, Targeting strategy for the Trem1 genomic locus and generation of Trem1-deficient mice
    • Supplementary Figure 2 - PDF file - 835K, TREM-1 expression on KC of WT mice increased after DEN administration
    • Supplementary Figure 3 - PDF file - 2.5MB, Deletion of TREM-1 down regulates genes associated with DNA repair and genes involved in hepatocellular carcinoma development
    • Supplementary Figure 4 - PDF file - 680K, Deletion of TREM-1 inhibits cytokine and chemokine production by bone marrow-derived macrophages stimulated with the product of necrotic hepatocytes (PNH)
    • Supplementary Figure 5 - PDF file - 7.2MB, The expression of TREM-1 in human liver KC
    • Supplementary Figure Legends 1-5 - PDF file - 19K
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Cancer Research: 72 (16)
August 2012
Volume 72, Issue 16
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The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
Juan Wu, Jiaqi Li, Rosalba Salcedo, Nahid F. Mivechi, Giorgio Trinchieri and Anatolij Horuzsko
Cancer Res August 15 2012 (72) (16) 3977-3986; DOI: 10.1158/0008-5472.CAN-12-0938

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The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
Juan Wu, Jiaqi Li, Rosalba Salcedo, Nahid F. Mivechi, Giorgio Trinchieri and Anatolij Horuzsko
Cancer Res August 15 2012 (72) (16) 3977-3986; DOI: 10.1158/0008-5472.CAN-12-0938
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